The ciliopathies are a group of >100 overlapping clinical disorders caused by defects in the primary cilium and its anchoring structure, the basal body. Although individually rare, this group contributes significantly to the population genetic disease burden, with some estimates placing their combined incidence to as much as 1:1000. Importantly, although some ciliopathies are lethal, most patients survive to adulthood, where they are faced with profound clinical challenges of managing multiple symptoms that include retinal degeneration, neurocognitive defects, obesity, diabetes and psychiatric illness. At present, there are no treatments and minimal palliative options. This proposal aims to take the first steps towards developing clinical assets that aspire to slow or arrest degenerative aspects of the ciliopathy pathology. Our work is grounded on two key observations. First, several recent studies have shown that ciliopathy proteins regulate the selective proteasome-mediated degradation of signaling components. Second, a recent genome-wide suppressor screen in human cells showed that suppression of the deubiquitinase USP35 could ameliorate ciliopathy-induced signaling defects. Validating these observations, suppression or deletion of USP35 in three zebrafish models of Bardet-Biedl syndrome (BBS), a model ciliopathy, attenuated several pathognomonic phenotypes, most prominently structural and trafficking defects in the photoreceptor with no apparent toxic side effects. These discoveries and models have been foundational to the formation of Rescindo Therapeutics, a biotech company whose mission is to develop suppressor screens and derivative molecules as rational therapeutic agents. During the past year, Rescindo has developed two reagents of potential clinical utility: an adeno-associated virus expressing shRNAs against human and mouse USP35 and antisense oligonucleotides against the same target. Here, we aim to test the utility of these tools in human cells and in mouse models as a pre-amble to designing clinical trials. Within our company, we will test the efficacy of each reagent to attenuate paracrine signaling in primary cells derived from patients with mutations in three different BBS genes. In parallel, and in collaboration with the Arshavsky laboratory at Duke, we will test whether each reagent can have a quantitative benefit in attenuating or extinguishing the progressive loss of photoreceptors in a mouse mode of BBS. Successful completion of these studies will provide the necessary data for the rational design of future trials and will represent a key step towards developing the first therapeutic assets for ciliopathies.